7. PROJECT SUMMARY/ ABSTRACT Dry eye syndrome is a common affliction of the eye that affects millions of people. Dry eye is brought on by aging, eye surgery or environmental exposure and is also an adverse effect of contact lens wear, and topical eye medications. Symptoms include pain, burning, itching, redness, sensitivity to light and other discomfort. If left untreated, severe cases may result in vision loss due to corneal scarring. New research from this research team, recently published in the NIH-supported journal PLOS ONE, suggests a new approach to treating dry eye. Using an experimental mouse model, the researchers found that the natural tear protein known as clusterin selectively binds to the ocular surface barrier disrupted by desiccating stress in an all-or-none manner, while also preventing further damage. Known properties of clusterin suggest it may further protect against the upstream effects of inflammatory cascade activation and subsequent squamous metaplasia. The proposed research will investigate this previously unrecognized, endogenous protective mechanism. The planned studies make use of the mouse experimental model and a quantitative functional assay for ocular surface barrier disruption, and take advantage of mouse genetics. The specific aims are: 1) to determine the molecular nature of clusterin intercalation into the ocular surface glycocalyx, and how it might relate to the all- or-none effect; 2) to document the role of clusterin in anti-proteolysis, the effects of proteolysis on the capacity for clusterin binding, and the relationship between the proteolytic and clusterin pathways; 3) to define the endogenous clusterin protection pathway and its role in maintaining an anti-inflammatory environment at the ocular surface. The impact of this research will be new basic science knowledge about the ocular surface barrier, how it is altered in disease, and mechanisms of protection by clusterin. The results will set the stage for clinical innovation.